Tuesday, 17 July 2012

Leprosy


Leprosy (Gk lepros, scaly – Hansen’s disease, Hansen was a Norwegian bacteriologist/leprologist) is a chronic granulomatous disease (the granulomas can be linear following nerves) caused by Mycobacterium leprae (M. Leprae) principally affecting  peripheral nerves and the skin (the bacteria have a predilection for cool skin). The disease has been endemic in India and the Far East since ancient times. It is generally a tropical infection. 86% of leprosy patients reside in six countries (India, Brazil, Indonesia, Myanmar “Burma”, Madagascar and Nepal). However, leprosy has not always been a tropical disease; it was endemic in Norway until the early 20th century. Leprosy can be seen outside the tropics as people migrate to live in other countries. Leprosy tends to be over-diagnosed in endemic countries and under-diagnosed in non-endemic countries. In any population it is important for the physician to know the normal range of skin colour and texture, the common endemic skin diseases that may coexist with leprosy and the common medical and artefactual practices that may cause lesions resembling those of leprosy.

The term ‘mycobacterium’ has been given to a large group of bacteria producing mould-like pellicles when grown on liquid media. All are slender, non-motile, aerobic, rods with a waxy coating that makes them resistant to most stains. Once stained, however, they are not easily decolourized (acid-fast). M. leprae has never been grown in vitro. Growth has been achieved in e.g. the nine-banded armadillo. This animal has provided mycobacteria for genetic and biochemical analysis and the production of trial vaccines. Recent work based on amino acid sequencing of M. leprae proteins suggests that there are subtle strain differences. The organism synthesizes a species-specific lipid, phenolic glycolipid (PGL).  The highly conserved Toll-like receptors on the surface of monocytes and macrophages recognize mycobacterial lipoproteins.   PGL-1 antibodies can be detected and seropositivity correlates with bacterial load measured by slit-skin smears. The assertion that  M. lepromatosis is a new leprosy-causing species is not proven.


Leprosy is a chronic disease with a long incubation period (many years).  Nasal discharges from untreated lepromatous leprosy patients, who are often undiagnosed for several years, are the main source of infection in the community. Infection probably occurs through the nose thus M. Leprae is inhaled, multiplies on the inferior turbinates and has a brief bacteraemic phase before binding to Schwann cells and macrophages. Accordingly, the nose seems to be both the portal of exit and the portal of entry.  The skin is unimportant in leprosy transmission. Subclinical infection with M. leprae is probably common and there is no reliable test for determining whether a person has encountered M. leprae and mounted a protective immune response. Self-healing often occurs in early monomacular tuberculoid cases.


Lepromatous leprosy represents a failure of cell-mediated immunity (CMI) specifically towards M. leprae with resultant bacillary multiplication, spread and accumulation of antigen in infected tissues. The absence of activated lymphocytes and macrophages means that nerve damage is slow and gradual in onset. In tuberculoid leprosy, CMI is strongly expressed, so that the infection is restricted to one or a few skin sites and peripheral nerves. Lymphocytic infiltration rapidly causes nerve damage. Between those two polar forms lie the borderline forms of disease, with the extent of disease reflecting the balance between CMI and bacillary load. Borderline patients (borderline tuberculoid, BT; borderline, BB; borderline lepromatous, BL) are immunologically unstable.


There are important determinants of leprosy risk e.g. genetic factors and BCG vaccination. There is substantial cross-reactivity between BCG and M. leprae. The variable protection induced by BCG is due to early contact with environmental mycobacteria priming the immune system and conferring protective immunity against M. leprae. Being HIV positive does not appear to confer increased susceptibility to leprosy. Patients with concomitant infections have the usual granuloma formation even with low circulating CD4 counts. Co-infected patients appear to be at increased risk of developing leprosy reactions and the borderline types of leprosy dominate the clinical picture. Leprosy may also present as an IRIS phenomenon in HIV-positive patients who have recently started ART.


In tuberculoid leprosy only nerves and skin show clinical evidence of disease; lesions are few, often solitary. The condition may be purely neural, with pain and swelling of the affected nerve followed by anaesthesia and/or muscle weakness and wasting. Alternatively, a skin lesion appears with or without evidence of nerve involvement. The typical lesion is a plaque that is conspicuous, erythematous, copper coloured or purple, with raised and clear-cut edges sloping towards a flattened and hypopigmented centre.  Dark skins may not show the erythema. The surface is dry, hairless and insensitive, and sometimes scaly. A thickened sensory nerve may be palpated or a thickened nerve trunk may be felt in the vicinity.  Less commonly the lesion is a macule, erythematous in light skins and hypopigmented in dark skins. Such macules have a dry, hairless and insensitive surface. In tuberculoid leprosy, the granulomas collect in foci surrounding neurovascular elements. The granuloma invades the papillary zone and may even erode the epidermis, but acid-fast bacilli (AFB) are not usually seen. In tuberculoid leprosy, bacillary multiplication is restricted to a few sites and bacilli are not easily found (paucibacillary type of leprosy).

Lepromatous leprosy represents a failure of cell-mediated immunity specifically towards M. leprae with resultant bacillary multiplication, spread and accumulation of antigen in infected tissues (multibacillary type of leprosy). The absence of activated lymphocytes and macrophages means that nerve damage is slow and gradual in onset. In lepromatous  leprosy, haematogenous spread of bacilli occurs to cool, superficial sites, including eyes, upper respiratory mucosa, testes, small muscles and bones of hands, feet and face, as well as peripheral nerves and skin (e.g. nose and ears). The first clinical manifestations of lepromatous leprosy are usually cutaneous because nerve damage is slow and gradual in onset, but even these cutaneous manifestations may go unnoticed by the patient, who often complains of other early symptoms; these include nasal stuffiness, discharge and epistaxis, and oedema of legs and ankles due to increased capillary stasis and permeability. Cutaneous signs comprise macules, papules, infiltration or nodules, or all four. Macules are small, multiple, erythematous or faintly hypopigmented. Nodules usually have normal skin colour but sometimes are erythematous. If the patient remains untreated the lines of the forehead become deeper as the skin thickens. The thickened skin, most marked over the forehead and other areas of the face, starts to develop folds (thrown into folds) which hang down in conjunction with nodules (producing leonine facies). By this time anaesthesia is extensive and is accompanied by anhydrosis. Excessive compensatory sweating from unaffected areas, especially the axillae, becomes obvious. Moreover, there is loss (or thinning) of eyebrows and eyelashes (madarosis), the nose may collapse due to septal perforation and loss of the anterior nasal spine, the voice becomes hoarse and the upper incisor teeth loosen or fall out.  A slow fibrosis of peripheral nerves results in nerve thickening and bilateral ‘glove and stocking’ anaesthesia but sensation of palms and soles is retained until late in the disease (it generally spares warm skin such as palms and soles and midline of the back). Testicular atrophy leads to infertility, erectile dysfunction and gynaecomastia.  Dermatofibroma-like (histoid)lesions are distinctive round, regular, cutaneous nodules that stand out on normal skin. They are characteristic of lepromatous leprosy relapse after treatment but they can be the presenting lesions. In lepromatous leprosy, there is thinning of epidermis and flattening of rete ridges between dermal papillae and the papillary layer of the dermis appears as a clear band (grenz zone), whilst deeper in the dermis lies the typical diffuse leproma consisting of foamy macrophages, with the addition of a few lymphocytes and plasma cells. The dermis contains enormous numbers of AFB, singly or in clumps (globi). With treatment, the leproma shows increased foamy change, vacuolates and breaks up into discrete foci with fibrocytes at the periphery. These foci shrink as treatment is continued and bacilli become fragmented and granular.  Despite the large numbers of organisms in the nerve there is only a small inflammatory response; ultimately the nerve fibroses and is hyalinised.


In borderline leprosy, skin lesions are intermediate in number between those of the two polar types already described, depending on the position of the patient on the borderline spectrum, and are distributed asymmetrically. They may take the form of macules, plaques, annular lesions or bizarre-shaped bands. Plaques with a ‘punched-out’ appearance are characteristic of the middle of the spectrum. Damage to structures other than skin and nerves will not be manifest clinically in borderline leprosy, even though bacilli may be present in other tissue. Borderline leprosy is the commonest type of disease encountered and is unstable and ‘down-grades’ towards lepromatous, especially if untreated, or ‘upgrades’ towards tuberculoid. The formation of small granulomas is characteristic of borderline leprosy. Left untreated, borderline patients will downgrade towards the lepromatous end of the spectrum


The transitory stage of leprosy called indeterminate leprosy occurs in those whose immunological state has not yet been determined, and histopathologically there is a scattered non-specific histiocytic and lymphocytic infiltration with some concentration around skin appendages. Rarely, a single bacillus will be found within a dermal nerve. The indeterminate phase may last for months or years before resolving or giving way to one of the determinate types of leprosy. The classic skin lesion in indeterminate leprosy is most commonly found on the face, extensor surface of the limbs, buttocks or trunk. Indeterminate lesions consist of one or more slightly hypopigmented or erythematous macules, a few centimetres in diameter, with poorly defined margins.


Pure neuritic leprosy presents with asymmetrical involvement of peripheral nerve trunks and no visible skin lesions; on histopathology of a cutaneous nerve biopsy, all types of leprosy are seen. It is seen most frequently, but not exclusively, in India and Nepal where it accounts for 5–10% of patients.

Type 1 lepra reaction is a cellular hypersensitivity and the change in cellular immunity of the patient may be in either direction. The term reversal is used for an increase in cellular immunity and a shift towards the tuberculoid pole. The term downgrading is used for a loss of cellular immunity and a shift towards the lepromatous pole. Type 1 lepra reactions occur in borderline disease and are characterized by acute neuritis and/or acutely inflamed skin lesions (inflammation starts within some of the existing skin lesions but new lesions can appear). Despite the fundamental difference between reversal and downgrading reactions, they are clinically indistinguishable without careful history (downgrading reactions occur before therapy or if the therapy is inadequate and reversal reactions occur in response to adequate therapy). It has been said that the patient undergoing reversal reaction (towards healing) does so “at the expense of his nerves”. In type 1 reaction, the changed skin lesions are not usually painful but the nerves can be EXTREMELY painful. In downgrading reactions, as cellular hypersensitivity is suppressed, type 2 reactions may TAKE OVER and the clinical picture becomes complicated. Type I reactions show an increase in lymphocytes and sometimes giant cells, as well as the formation of small clusters of epithelioid cells. This is the picture seen in the usual upgrading reaction. In downgrading reactions there is replacement of lymphocytes and epithelioid cells by collections of macrophages, and there is a corresponding increase in the number of bacilli.


Type 2 lepra reaction is a humoral hypersensitivity and is not associated with a shift along the spectrum. It is due to Ag-Ab reaction with the formation of immune complexes and gives rise to erythema nodosum leprosum [ENL] (commonest on the face and extensor surfaces of the limbs). ENL occurs in patients with multibacillary disease (borderline lepromatous leprosy and lepromatous leprosy). ENL may occur spontaneously or whilst on treatment and actually up to 50% of lepromatous leprosy patients may experience ENL. ENL manifests most commonly as painful red nodules on the face and extensor surfaces of limbs. Lesions last for a few days and are succeeded by crops of new ones. In contrast to type 1 reaction, the actual leprosy lesions appear unchanged clinically and the new lesions are commonest on the face and extensor surfaces of the limbs, but may also be seen elsewhere. Attacks are often acute at first, but may be prolonged or recurrent over several years and eventually quiet but insidious! The lesions may be superficial or deep, with suppuration ulceration or brawny induration when chronic. ENL is a systemic disorder, producing fever and malaise. It may be accompanied by uveitis, dactylitis, arthritis, neuritis, lymphadenitis, myositis and orchitis. In terms of nerve damage, ENL is usually less serious than type 1 reactions but it is often more prolonged.   ENL shows a mixed dermal infiltrate of neutrophils and lymphocytes superimposed on collections of macrophages. There are relatively more T lymphocytes of helper-inducer type (CD4+) than in non-reactive lepromatous leprosy. This appears to be due to an absolute reduction in the number of T-suppressor (CD8+) cells, which predominate in lepromatous leprosy. Histopathologically, the signature cell of ENL is the neutrophil. A vasculitis is often present.


Type 3 lepra reaction or the Lucio reaction/phenomenon (erythema necroticans) only occurs in patients with Lucio leprosy, a variety of lepromatous leprosy “diffuse lepromatous leprosy” [the skin of the whole body becomes diffusely thickened, rendering it stiff and smooth as in scleroderma and it is the purest form of lepromatous leprosy]. It is due to infarction consequent upon deep cutaneous vasculitis centred upon M. Leprae in vascular endothelial cells, and causing the appearance of irregularly shaped erythematous patches which become dark and heal, or form bullae and necrose, leaving deep painful ulcers that are slow to heal (large polygonal sloughing ulcerations, usually on the legs). The systemic upset is severe and can be fatal. In Lucio’s phenomenon the endothelial cells and macrophages in the dermis, contain numerous bacilli. There is usually only a mild inflammatory infiltrate, with fewer neutrophils than in ENL.


The posterior tibial nerve is the most frequently affected nerve. Posterior tibial nerve damage is serious because it causes paralysis and contracture of the small muscles of the foot and anaesthesia of the sole.


Blindness due to leprosy is a devastating complication, especially for a patient with anaesthetic hands and feet. Eye damage results from both nerve damage and bacillary invasion.


The term ainhum (Yoruba Nigerian, ‘to saw’) is applied to a specific type in which a painful constriction of the fifth toe occurs in adults, with eventual spontaneous amputation. Pseudoainhum is the term applied to other constricting bands which are congenital or secondary to another disease. Leprosy is a cause of pseudoainhum.

Leprosy is rarely a primary cause of death, but patients have a standardized death rate at least twice that of the general population due to the indirect secondary effects of the disease.


The diagnosis of leprosy is usually made clinically on the basis of two out of three cardinal signs, or by the demonstration of AFB in slit-skin smears (fluid and pulp from the dermis, collected on one side of the blade, are gently smeared on to a glass slide. The smear is then fixed over a flame and stained. A bloody smear is useless), or by histopathology typical of leprosy. The cardinal signs are: 1) anaesthesia of a skin lesion or in the distribution of a peripheral nerve, or over dorsal surfaces of hands and feet 2) thickened nerves, especially at the sites of predilection 3) typical skin lesions. The AFB load of a patient is determined by modified Ziehl–Neelsen staining of slit-skin smears. When performing a skin biopsy, the incision should be made down to subcutaneous fat, so that the whole depth of the dermis is included, otherwise leprous changes in the deeper layers of the dermis will be missed. PCR probes have been developed for the detection of M. leprae DNA in tissues from leprosy patients and it is possible, using a PCR–single strand polymorphism technique, to identify rifampicin-resistant isolates within hours. The use of PGL-1 antibody testing may be useful in assessing paucibacillary patients who are smear negative. Note that lepromatous patients produce a range of autoantibodies, both organ-specific (directed against e.g. nerve and testis), and non-specific, such as cardiolipin.


The AFB load of a patient is determined by modified Ziehl-Neelsen staining of slit-skin smears. Suspect lesions, and sites commonly affected in lepromatous leprosy, should be sampled (forehead, earlobes, chin, extensor surface of the forearm, buttocks and trunk). The density of bacilli is expressed using a logarithmic scale, extending from very few AFB to many per high-power field. A mean score, the bacterial index (BI), is derived by adding the scores from each site and dividing by the number of sites sampled. In untreated lepromatous leprosy, the BI is 5. or 6. The BI falls to zero in TT disease. With treatment, bacilli disappear from BB lesions in a few months and from BL lesions in a year or two. It may take 6–10 years for the last bacillary remnants to disappear from the skin in LL.
Lepromin test: A crude, semi-standardized preparation of heat killed bacilli from a lepromatous nodule or infected armadillo liver is used by intra-dermal injection. The lepromin test is a non-specific test of occasional value in classifying a case of leprosy. It is strongly positive in TT, weakly positive in BT, negative in BB, BL and LL, and unpredictable in indeterminate leprosy. It is not diagnostic, since it can be positive in people with no evidence of leprosy.


Differential diagnosis of leprosy depends on the type of lesion (e.g. in macular lesions: diseases such as vitiligo, pityriasis alba, and pityriasis versicolor – in plaques and annular lesions: diseases such as tinea corporis, sarcoidosis and cutaneous tuberculosis – in nodules:  diseases such as cutaneous leishmaniasis – in neural lesions: diseases such as diabetes and HIV infection). Mycosis fungoides should also be considered.
There are five main principles of treatment: 1) Stop the infection with chemotherapy 2) Treat reactions and reduce the risk of nerve damage 3) Educate the patient to cope with existing nerve damage, in particular anaesthesia 4) Treat the complications of nerve damage 5) Rehabilitate the patient socially and psychologically.


Antibacterial treatment for leprosy is highly effective. Drugs recommended are dapsone, rifampicin, and clofazimine. Other drugs with significant activity against M. leprae include ofloxacin, minocycline and clarithromycin, but none of these are as active as rifampicin; at present they should be reserved as second-line drugs for leprosy. A single-dose triple-drug combination (rifampicin, ofloxacin and minocycline) has been tested in India for patients with single skin lesions; although the single dose treatment is less effective than the conventional 6-month treatment for paucibacillary leprosy, it is an operationally attractive field regimen and has been recommended for use by the WHO.


A three-drug regimen [Rifampicin – Dapsone – Clofazimine]   is recommended for multibacillary leprosy (lepromatous, borderline-lepromatous, and borderline leprosy) and a two-drug regimen [Rifampicin – Dapsone] for paucibacillary leprosy (borderline-tuberculoid, tuberculoid, and indeterminate).


Multibacillary leprosy should be treated for 24 months. The recommended length of treatment for multibacillary patients has dropped from 24 months to 12 months by some. There was no controlled trial data to guide this decision, but the classification of multibacillary patients had been widened, so some patients who would previously have received paucibacillary treatment for 6 months are now receiving multibacillary treatment for 12 months. Increased doses of clofazimine 100 mg 3 times daily for the first month with subsequent reductions, are also useful but may take 4–6 weeks to attain full effect.

Paucibacillary leprosy should be treated for 6 months. If treatment is interrupted the regimen should be recommenced where it was left off to complete the full course.





New proposals include testing a common 6-month regimen of dapsone, clofazimine and rifampicin for all patients. This would simplify leprosy treatment but would give some patients a third drug that they do not need, and under-treat patients with a high bacterial load.


Neither the multibacillary nor the paucibacillary antileprosy regimen is sufficient to treat tuberculosis.



Treatment should be continued unchanged during both type I and type II (erythema nodosum leprosum) reactions. During type I reactions neuritic pain or weakness can herald the rapid onset of permanent nerve damage. Treatment with prednisolone (initially 40–60 mg daily) should be instituted at once. However, some patients with active neuritis will develop permanent nerve damage despite treatment with prednisolone. Mild type II reactions may respond to aspirin. Severe type II reactions may require corticosteroids; thalidomide is also useful in men and post-menopausal women who have become corticosteroid dependent, but it should never be used in women of child-bearing potential (significant teratogenic risk).


Treatment of Lucio’s phenomenon includes the standard multidrug therapy for lepromatous leprosy (rifampicin, clofazimine and dapsone). Control of infection and attention to fluid and electrolyte balance are important. Prednisolone may be required to control the reaction. It fails to respond to thalidomide. Response to treatment is often reported as poor, with severe morbidity and frequent deaths, but numbers of reported cases are small. Plasmapheresis reported as helpful in unremitting patients.


This page was last updated in October 2013.

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Main Works of Reference List (The First eight are my Favourites)

  • British National Formulary
  • British National Formulary for Children
  • Guidelines (BAD - BASHH - BHIVA - Uroweb)
  • Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health
  • Oxford Handbook of Medical Dermatology
  • Rook's Textbook of Dermatology
  • Simple Skin Surgery
  • WHO manuals (Male infertility and Semen analysis)
  • A Concise Atlas of Dermatopathology (P Mckee)
  • Ackerman's Resolving Quandaries in Dermatology, Pathology and Dermatopathology
  • Andrews' Diseases of the Skin
  • Andrology (Nieschlag E FRCP, Behre M and Nieschlag S)
  • Bailey and Love's Short Practice of Surgery
  • Davidson's Essentials of Medicine
  • Davidson's Principles and Practice of Medicine
  • Fitzpatrick's Colour Atlas and Synopsis of Clinical Dermatology (Klaus Wolff FRCP and Richard Allen Johnson)
  • Fitzpatrick’s Dermatology in General Medicine
  • Ganong's Review of Medical Physiology
  • Gray's Anatomy
  • Hamilton Bailey's Demonstrations of Physical Signs in Clinical Surgery
  • Hutchison's Clinical Methods
  • Lever's Histopathology of the Skin
  • Lever's Histopathology of the Skin (Atlas and Synopsis)
  • Macleod's Clinical Examination
  • Martindale: The Complete Drug Reference
  • Oxford Handbook of Clinical Examination and Practical Skills
  • Sexually Transmitted Diseases (Holmes K et al)
  • Statistics in Clinical Practice (D Coggon FRCP)
  • Stockley's Drug Interactions
  • Treatment of Skin Disease: Comprehensive Therapeutic Strategies
  • Weedon's Skin Pathology
  • Yen & Jaffe's Reproductive Endocrinology